This invention relates the use of a combination of a rapamycin and an antiestrogen in the treatment or inhibition of estrogen receptor positive carcinoma, particularly breast and ovarian cancer.
Breast cancer is a leading cause of female cancer deaths in the world. The growth of some human breast cancer cells is under hormonal control. Substantial evidence suggests that estrogen promotes the development of breast cancer. The biological effect of estrogen in the breast is mediated by estrogen receptor (ER), which is a member of a large family of ligand-inducible transcription factors. Upon binding to its receptor, the ligand initiates the dissociation of heat shock proteins from the receptor, receptor dimerization, phosphorylation, and binding to DNA response elements of target genes. After binding to DNA, ER differentially regulates transcription of target genes with or without other transcription factors and coactivators/corepressors. Estrogen action can be partially blocked by antagonists (antiestrogens) which act through ER in a way that is competitive with estrogen but fails to activate genes that promote cell growth. The antiestrogen tamoxifen (Tam) has been the first-line therapy in the treatment and management of breast cancer based on the estrogen responsiveness for stimulation of tumor growth. Unfortunately, the effectiveness of Tam therapy is hampered by its agonist activity in other tissues such as the uterus and side effects like hot flashes. There is a need to develop new antiestrogens or to develop optimal combinations of antiestrogens with other therapeutic agents to achieve better efficacy and reduce side effects.
Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. Nos. 3,929,992; and 3,993,749]. Additionally, rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity.
A rapamycin ester, rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid [disclosed in U.S. Pat. No. 5,362,718], also known as CCI-779, has been shown to have antitumor activity against a variety of tumor cell lines, in in vivo animal tumor models, and in Phase I clinical trials. [Gibbons, J., Proc. Am. Assoc. Can. Res. 40: 301 (1999); Geoerger, B., Proc. Am. Assoc. Can. Res. 40: 603 (1999); Alexandre, J., Proc. Am. Assoc. Can. Res. 40: 613 (1999); and Alexandre, J., Clin. Cancer. Res. 5 (November Supp.): Abstr. 7 (1999)].
Non-uterotrophic antiestrogens have been reported to have antitumor activity [see, U.S. Pat. No. 5,998,402]. 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperdin-1-yl-ethoxy)-benzyl-1H-indol-5-ol, also known as ERA-923, has been reported as being developed for the treatment of estrogen receptor positive metastatic breast cancer. [Gandhi, T., 2000 ASCO Program/Proceedings, Abstract 875, (May 2000)].